The novel viral respiratory illness named COVID-19 caused by SARS-CoV-2, first reported in Wuhan, China, has presented as one of the greatest challenges for disease control and eradication in modern history. The number of infected cases and the fatalities are increasing day by day with the latest WHO situation report-132 putting the number of infected cases as over 5.9 million with the death toll having crossed 367,000 worldwide. Initially, all non-emergency healthcare services were advised to be withheld to try and control disease transmission. However, given the scale of disease spread across countries, and the expected prolonged period before control, it is likely all healthcare services, both essential and elective, will need to resume amidst the ongoing pandemic. In this situation, it is important to consider plausible options of prophylaxis for high-risk groups and healthcare workers. As medical professionals, we are at a higher risk of being exposed to the virus as compared to the rest of the population, as even among asymptomatic persons there is a high level of shedding of the SARS-CoV-2 virus, which increases the risk of transmission. Thus, prophylaxis or prevention of infection is an important strategy in controlling this pandemic. Across the world, guidelines are being released with regard to use of personal protective equipment (PPE), out-patient, in-patient, and operating room procedures to reduce the risk of infection. However, despite all the protective equipment and guidelines, the number of people infected by SARS-CoV-2 including healthcare professionals is rising by the day. Hence, additional prophylactic strategies including the use of pharmacological agents, managing nutritional deficiencies, and adopting well-being practices need to be explored to mitigate the spread of the infection.
This article aims to provide a brief update on viral transmission at the mucosal surfaces and stratified approaches to mucosal and systemic prophylaxis against SARS-CoV-2 infection/COVID-19. We hypothesize that the following approaches that are based on peer-reviewed published scientific literature could possibly help decrease the chances of contracting the infection or reduce the severity of its sequelae.
Update on viral transmission and systemic risk factors of severity
Severe acute respiratory syndrome associated coronavirus (SARS-CoV) is a part of a family of human coronaviruses (HCoV), which are enveloped, single-stranded RNA viruses. It is transmitted primarily via the respiratory route, both by direct contact or via aerosols from infected people. This has also been proven for the SARS-CoV-2 which causes COVID-19 wherein droplets and aerosols from nasopharyngeal and oropharyngeal tracts of infected people can be a source of infection. As the SARS-CoV-2 has been found in feces as well, other modes of transmission such as a feco-oral route is also a biological plausibility.
The status of the cells in mucosal surfaces contributes toward susceptibility to viral infection and the severity of the disease. Angiotensin-converting enzyme 2 (ACE2), TMPRSS2 and Cathepsin B/L are essential for the entry of SARS-CoV-2 into host cells and hence are attractive targets for prophylaxis and therapeutics. SARS-CoV-2 binds to the host cells via the interaction of the spike protein, S of the virus to ACE2 on the host cells. Post-binding, the viral entry into the cells are facilitated by proteolytic cleavage of virus S protein by two independent host proteases: (i) TMPRSS2, a transmembrane serine protease, facilitates the fusion of viral and host cell membranes at the target cell surface to facilitate entry; (ii) Cathepsin B and L are endosomal cysteine proteases that allows the fusion of viral and host endosomal membranes, an event that precedes the release of viral genetic material into the host cell and subsequent replication of the virus.
The definite anatomical and host receptor links through the respiratory and ocular mucosa increase the tropism of respiratory viruses for these two areas. In addition, the anatomical connect formed by the nasolacrimal system and the distribution of permissive cellular receptors across both the respiratory tract and ocular mucosa increase the risk of infection. Epithelial cell glycoproteins bearing terminal sialic acids (SA) like 2-6-linked SA and 2-3-linked SA serve as the cellular receptor for different respiratory viruses. Though studies in the past were able to demonstrate the cell surface ACE2 only in respiratory mucosa and posterior parts of the eyeball, a recent study has shown the presence of these cell surface proteins in the conjunctiva and corneal epithelium as well. Therefore, not surprisingly as in the previous SARS coronavirus outbreak, the possibility of transmission of SARS-CoV-2 has also been reported through the ocular mucosa. An ophthalmologist in China was reported to have conjunctivitis, which was followed by a systemic SARS-CoV-2 infection. Following these initial reports, several studies were undertaken to study the possibility of transmission through the ocular surface and of tears being a carrier of the virus. Though a study done at Singapore could not find RT-PCR positivity for the virus in the tear fluid of COVID-19 patients, some other studies have been able to show RT-PCR positivity for the virus in tears. In addition, different studies have reported varying proportions of COVID-19 infected patients showing conjunctival involvement. The above findings show that the ocular surface could be infected through aerosols from infected patients and further transmit the infection to the respiratory tract through the nasolacrimal duct. As conjunctivitis could potentially be a presenting symptom of COVID-19, guidelines to approach conjunctivitis during this pandemic have also been made.
Another important finding from a recent meta-analysis published from China was that there is significantly higher odds of severe COVID-19 infections being associated with systemic comorbidities such as hypertension, diabetes, cardiovascular, and respiratory system disease. Additionally, it has been shown that elderly and immunocompromised people are more severely affected by this illness. Based on these, and a few other published associated risk factors, we have categorised healthcare workers into low, moderate, and high-risk groups [Fig. 1]. This would help decide on what level of prophylaxis they might need. On the basis of scientific evidence, we have tried to provide a comprehensive prophylaxis algorithm [Fig. 2]. All of these measures are recommended in addition to the use of PPE and existing guidelines and precautions suggested by literature from around the world. Targeted modulation with intent to enhance genes or activity of factors that would prevent viral entry and replication in the mucosa would severe as an ideal approach for pharmacological prophylaxis. The types of prophylaxis could either be a direct approach at the mucosal surfaces or indirectly via a systemic approach or both.
Respiratory mucosal prophylaxis
The viral endocytosis of the SARS-CoV in the human cells is shown to be pH dependent. Irrigation of the nasopharynx and gargle of the oropharynx with hypertonic saline, twice daily or before and after patient exposure, could alter the pH of these environments and possibly decrease viral attachment and entry into cells. Nasal hypertonic salt is easily available as sachets over-the-counter, which can be diluted in lukewarm water to make hypertonic saline for immediate use. A related concept was utilized previously in the development of a novel mask, which was incorporated with sodium chloride crystals to prevent viral aerosol transmission. The authors claim the mask has a very high filtration capacity and potential ability to deactivate the pathogen, thereby preventing spread of the virus from discarded masks.
Anti-histaminic agents such as chlorpheniramine maleate (CPM) have been shown to effectively prevent viral transmission of a broad spectrum of influenza viruses through the respiratory mucosa. They do not interfere with the viral attachment on to the cell surface, but inhibit the process of endocytosis, by which the virus enters into the host cell. SARS-CoV-2 viruses, though they attach onto cells using a different cell surface protein, have a similar process of endocytosis and therefore CPM can lower the risk of acquiring the COVID-19 infection. In healthcare workers with allergies and high IgE, this can be potentially beneficial as a prophylaxis. Anti-histaminic drugs such as Olopatadine and Azelastine are also medications which selectively inhibit H1 histamine receptors, similar to CPM. Olopatadine, in addition, has a mast cell stabilizing property too. Both Azelastine and Olopatadine are also available as nasal sprays allowing for easy and targeted application to the nasal mucosa. We recommend starting the medication in consultation with their allergy-immunology and ENT specialists as the dosage and generic drug has to be decided and titrated depending on individual requirements, tolerability and safety profile.
Ocular mucosal prophylaxis
Very recent findings confirm the expression of viral entry-associated genes ACE2 and TMPRSS2 in ocular mucosal surface cells (corneal and conjunctival) in addition to respiratory and intestinal epithelial cells, thus suggesting ocular surface as an additional route of SARS-CoV-2 transmission. The anatomical connection of the ocular surface mucosa to the respiratory tract mucosa via the nasolacrimal duct as discussed previously further emphasizes the possibility of ocular-respiratory route of transmission. Hence, targeting these viral entry-associated proteins on the ocular surface would be beneficial in the prevention of SARS-CoV-2 infection via the surface of the eye. Certain medications used as eye drops for other conditions including hydroxychloroquine and trehalose may have beneficial prophylactic effects against SARS-CoV-2 by modulating the factors that facilitates viral entry. Hydroxychloroquine can prevent viral attachment and entry into host cells by impairing glycosylation of ACE2, thus disrupting the interaction between S protein and ACE2. It also blocks clathrin-mediated viral endocytosis and prevents fusion of viral and host cell endosomal membranes by preventing endosomal acidification (by increasing endosomal pH), an event that is critical for Cathepsin B/L activity [Fig. 3].
Trehalose, a simple plant based sugar known to modulate autophagy is also a widely used ocular pharmaceutical agent that is used as an eye drop. It is known for its anti-viral properties, such as induction of type 1 interferons, facilitating lysosomal degradation of intracellular virus, reducing viral entry by decreasing the expression of host cell surface proteins that facilitates the attachment of virus to the cells and reducing cathepsin activity [Fig. 3]. Autophagy induction is a newer phenomenon documented by several studies. Trehalose is one such drug which by means of induction of autophagy, provides an anti-inflammatory milieu to the ocular surface. However, one study did report that trehalose-mediated autophagy impaired anti-viral response in airway epithelial cells.
The anti-viral properties of ocular pharmaceutical agents discussed suggests that these agents can potentially prevent an aerosol based viral infection of the ocular surface. However, it is important to investigate the anti-viral potency at the doses used in ocular formulations. Both Trehalose 3% (4–6 times a day) and chloroquine 0.03% (twice a day) eye drops have been used in the treatment of dry eyes. While the long-term use of these medications topically has been shown to be safe, one report of probably excessive unmonitored use of chloroquine drops has been shown to result in a sterile corneal ulcer. Trehalose eye drop has been shown to alter tear film thickness up to 240 min after instillation. Considering this, Trehalose can either be used in a 3 h application or specifically around an hour before an expected exposure to a patient.
As discussed in the respiratory prophylaxis, anti-histamines could also be potentially used as an ocular prophylaxis. Anti-histamine eye drops, such as Olopatadine 0.1% eye drops (twice daily), is routinely used in patients with eye allergies. Even in long-term use and prophylactic use for ocular allergies, the drug is known to be safe. In the context of COVID-19, medications such as this could potentially have a role in decreasing the ocular route of transmission.
Interferons (IFNs) are endogenous proteins which have anti-viral activity by blocking viral protein synthesis and degrading viral RNA. The use of type 1 interferons (IFN) in the management of SARS-CoV and MERS-CoV has been well explored and has been found to significantly decrease viral shedding. More recent work has shown the effectiveness of the IFNalpha in disease resolution in COVID-19 patients and for prophylaxis. Another Type 1 IFN, Interferon alpha2b is already being used topically in the context of ocular surface squamous neoplasia (OSSN). Though it is relatively safe, adverse events such as follicular hyperplasia and corneal erosions have been documented. By means of its anti-viral activity, though Type 1 IFN alpha2b eye drops could theoretically decrease the chance of ocular COVID-19 infection and viral shedding, further research on its safety as a prophylaxis in normal eyes is needed before it can be repurposed for this indication. Nevertheless, this could be one potential ocular prophylactic agent in the making.
Povidone-iodine has been shown to have potent virucidal activity against a number of viruses, including SARS-CoV and MERS-CoV coronaviruses. It has been advocated for use as a prophylaxis for healthcare workers in addition to PPE in the form of nasal irrigation using 0.4% povidone-iodine solution and oral/oropharyngeal wash using 10 mL of 0.5% povidone-iodine solution. To further reduce the risk of cross-infection in the operation theatre, the American Academy of Ophthalmology has advised ophthalmologists to continue the use of 5% povidone-iodine in the patient's eye prior to surgery. This would reduce the viral load in the eye and decrease the potential risk of aerosolizing viral particles. However, care must be taken in refractive surgery as povidone-iodine is a potential cause for diffuse lamellar keratitis (DLK) post-laser in situ keratomileusis (LASIK). Healthcare workers who work in close proximity to patients, and who are exposed to large aerosol loads and can potentially stand to benefit from these repurposed topical medications.
There are a few systemic agents which have shown scientific basis for use as a prophylaxis against SARS/CoV-2.
Oral Hydroxychloroquine (HCQ) has been approved by ICMR (Indian Council of Medical research) for prophylactic use in healthcare workers at a starting dose of 400 mg twice a day on the first day, followed by 400 mg weekly for the next 7 weeks. At doses of <5 mg/kg, the drug is relatively safe and long-term irreversible side effects of retinal toxicity are noted only at doses >6.5 mg/kg/day over a cumulative period of over 5 years. However, even at regular prescribed doses, those with cardiac arrhythmias, G6PD deficiency, pre-existing renal/hepatic/retinal damage, and those on tamoxifen therapy should exercise caution, while there is no ophthalmological concern in short-term use. A basic medical evaluation is advisable for predisposing conditions of such life threatening adverse effects prior to initiating this prophylaxis.
Turmeric has been in dietary use in India since several centuries. Its active ingredient, Curcumin, has been studied extensively and has been shown to have anti-viral, anti-bacterial, anti-inflammatory, and anti-oxidant properties. In a study published from Taiwan, curcumin has been found to exert mild inhibitory effect on the replication of SARS-CoV. In addition, it also exerts positive effects in metabolic syndrome by lowering blood sugar and lipid levels, thus controlling systemic risk factors for developing severe COVID-19 infection. The allowable daily intake of curcumin is 3 mg/kg/day. Also important to know that Curcumin in combination with black pepper has a 2,000% better bio-absorption of curcumin and is available as an oral supplement. When dosage exceeds over 500 mg/day, adverse effects as nausea, rash, diarrhoea, and headache have been reported.
Recently, Amantadine, an FDA approved drug for treatment of influenza and Parkinson disease has shown potential repurposed application in the management of SARS/CoV-2 as it affects steps in the viral entry by altering cathepsin-mediated pathways. Further studies are needed before it can come in to use as a prophylactic agent during this pandemic.
General wellbeing and vitamin D check
Multicentric data from North America and Europe on COVID-19 severity/mortality has shown low systemic vitamin D levels to be associated with higher COVID-19 severity due to a heightened cytokine storm. Vitamin D has been shown to play an important role in immune response to infections, by modulating inflammatory cytokine production, monocyte differentiation among other actions. Deficiency of Vitamin D has also been independently linked to increased viral respiratory infections. Hence, Vitamin D supplementation should be considered an important prophylactic measure for COVID-19, particularly for Vitamin D deficient healthcare workers. Intramuscular or oral supplementation of Vitamin D should be initiated based on severity of deficiency. However, unregulated high doses are to be strictly avoided as it can lead to hypercalcemia and related complications. It is also worthwhile to improve overall micronutrient status, such as Vitamin A, C, B6, B12 and trace elements such as iron, zinc, copper, and omega-3 fatty acids as they have been shown to play an important role in protecting against viral infections. We have focussed on Vitamin D as it has been specifically studied in the context of COVID-19. Adhering to recommended dosage of these micronutrients is important and overuse of such over the counter multivitamin tablets should be strictly avoided.
Systematic review of yoga and physical activity (>30 min/day) has been scientifically documented to improve the immune status/response in adults. Meta-analysis has also shown that yoga can significantly decrease diastolic blood pressure and lipid levels, which are risk factors for severe form of COVID-19 infection. Any form of yoga and physical activity suiting the individual's lifestyle is strongly encouraged to be undertaken to strengthen our ability to deal with the infection.
All of the agents discussed and represented in Figs. 2 and 3 have shown scientific basis for a potential role as a prophylaxis against developing viral infections. During a pandemic, it is practically difficult to conduct large-scale randomized controlled trials (RCT) to generate scientific evidence. Hence, we can use allied research and existing scientific knowledge to derive possible therapeutic and prophylactic measures. At this point, they can be said to hypothetically decrease the risk of SARS-CoV-2 transmission and COVID-19 associated morbidity or mortality. Over time, these require more studies and data to validate them. These agents or measures have to be customized based on the health workers' risks and level of exposure. In summary, while adequate and appropriate use of PPE and avoiding inadvertent unprotected exposure to the virus are still the key stones in the approach to prevention, these additional prophylactic measures could play an adjunct role in stemming the spread of the infection.
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Conflicts of interest
There are no conflicts of interest.
1. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al A novel coronavirus from patients with pneumonia in China, 2019 N Engl J Med. 2020;382:727–33
2. World Health Organization (WHO) Coronavirus disease (COVID-19) Situation Report – 132. Data as received by WHO from national authorities by 10:00 CEST, 31 May 2020.
3. AIOS. AIOS Operational guidelines for Ophthalmic Practice during COVID-19 outbreak 2020.
4. James C. Important coronavirus updates for ophthalmologists Am Acad Ophthalmol. 2020
5. CDC. Interim Operational Considerations for Public Health Management of Healthcare Workers Exposed to or with Suspected or Confirmed COVID-19: Non-US Healthcare Settings. 2020Last accessed on 2020 May 14 Available forom: https://wwwcdcgov/coronavirus/2019-ncov/hcp/non-us-settings/public-health-management-hcw-exposedhtml
6. Gandhi M, Yokoe DS, Havlir DV. Asymptomatic transmission, the Achilles' heel of current strategies to control Covid-19 N Engl J Med. 2020;382:2158–60
7. AIOS. Ophthalmic Practice Guidelines in the Current Context of COVID-19. 2020
8. van der Hoek L. Human coronaviruses: What do they cause? Antivir Ther. 2007;12:651–8
9. Peiris JS, Yuen KY, Osterhaus AD, Stöhr K. The severe acute respiratory syndrome N Engl J Med. 2003;349:2431–41
10. WHO. Modes of transmission of virus causing COVID-19: Implications for IPC precaution recommendations. 2020Last accessed on 2020 May 14 Available from: https://wwwwhoint/publications-detail/modes-of-transmission-of-virus-causing-covid-19-implications-for-ipc-precaution-recommendations
11. Zhang W, Du RH, Li B, Zheng XS, Yang XL, Hu B, et al Molecular and serological investigation of 2019-nCoV infected patients: Implication of multiple shedding routes Emerg Microbes Infect. 2020;9:386–9
12. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and Is blocked by a clinically proven protease inhibitor Cell. 2020;181:271–808
13. Heurich A, Hofmann-Winkler H, Gierer S, Liepold T, Jahn O, Pöhlmann S. TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the severe acute respiratory syndrome coronavirus spike protein J Virol. 2014;88:1293–307
14. Hoffmann M, Kleine-Weber H, Pöhlmann S. A multibasic cleavage site in the spike protein of SARS-CoV-2 is essential for infection of human lung cells Mol Cell. 2020;78:779–84e5
15. Ou X, Liu Y, Lei X, Li P, Mi D, Ren L, et al Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV Nat Commun. 2020;11:1620
16. Padmanabhan P, Desikan R, Dixit NM. Targeting TMPRSS2 and Cathepsin B/L together may be synergistic against SARS-CoV-2 infection ChemRxiv. 2020 doi: 1026434/chemrxiv12213125v2
17. Belser JA, Gustin KM, Maines TR, Pantin-Jackwood MJ, Katz JM, Tumpey TM. Influenza virus respiratory infection and transmission following ocular inoculation in ferrets PLoS Pathog. 2012;8:e1002569
18. Bitko V, Musiyenko A, Barik S. Viral infection of the lungs through the eye J Virol. 2007;81:783–90
19. Shinya K, Ebina M, Yamada S, Ono M, Kasai N, Kawaoka Y. Avian flu: Influenza virus receptors in the human airway Nature. 2006;440:435–6
20. van Riel D, Munster VJ, de Wit E, Rimmelzwaan GF, Fouchier RA, Osterhaus AD, et al H5N1 virus attachment to lower respiratory tract Science (New York, NY). 2006;312:399
21. Choudhary R, Kapoor MS, Singh A, Bodakhe SH. Therapeutic targets of renin-angiotensin system in ocular disorders J Curr Ophthalmol. 2017;29:7–16
22. Sungnak W, Huang N, Becavin C, Berg M, Queen R, Litvinukova M, et al SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes Nat Med. 2020;26:681–7
23. Zhou L, Xu Z, Castiglione GM, Soiberman US, Eberhart CG, Duh EJ. ACE2 and TMPRSS2 are expressed on the human ocular surface, suggesting susceptibility to SARS-CoV-2 infection BioRxiv. 2020 doi: 101101/20200509086165
24. Loon SC, Teoh SC, Oon LL, Se-Thoe SY, Ling AE, Leo YS, et al The severe acute respiratory syndrome coronavirus in tears Br J Ophthalmol. 2004;88:861–3
25. Lu CW, Liu XF, Jia ZF. 2019-nCoV transmission through the ocular surface must not be ignored Lancet (London, England). 2020;395:e39
26. Post SCM. Chinese expert who came down with Wuhan coronavirus after saying it was controllable thinks he was infected through his eyes 2020Last accessed on 2020 May 10 Available from: https://wwwscmpcom/news/china/article/3047394/chinese-expert-who-came-down-wuhan-coronavirus-after-saying-it-was
27. ISeah IYJ, Anderson DE, Kang AEZ, Wang L, Rao P, Young BE, et al Assessing Viral Shedding and Infectivity of Tears in Coronavirus Disease 2019 (COVID-19) Patients Ophthalmology. 2020 doi: 101016/jophtha202003026
28. Seitzman GD, Doan T. No time for tears Ophthalmology. 2020 S0161-6420(20)30314-6 doi: 101016/jophtha202003030
29. Wu P, Duan F, Luo C, Liu Q, Qu X, Liang L, et al Characteristics of ocular findings of patients with coronavirus disease 2019 (COVID-19) in Hubei Province, China JAMA Ophthalmol. 2020;138:575–8
30. Xia J, Tong J, Liu M, Shen Y, Guo D. Evaluation of coronavirus in tears and conjunctival secretions of patients with SARS-CoV-2 infection J Med Virol. 2020 doi: 101002/jmv25725
31. Sun X, Zhang X, Chen X, Chen L, Deng C, Zou X, et al The infection evidence of SARS-COV-2 in ocular surface: A single-center cross-sectional study medRxiv. 2020Last accessed on 2020 May 11 doi: 101101/2020022620027938
32. Qing H, Li Z, Yang Z, Shi M, Huang Z, Song J, et al The possibility of COVID-19 transmission from eye to nose Acta Ophthalmol. 2020;98:e388
33. Shetty R, D'Souza S, Lalgudi VG. What ophthalmologists should know about conjunctivitis in the COVID-19 pandemic? Indian J Ophthalmol. 2020;68:683–7
34. Yang J, Zheng Y, Gou X, Pu K, Chen Z, Guo Q, et al Prevalence of comorbidities and its effects in coronavirus disease 2019 patients: A systematic review and meta-analysis Int J Infect Dis. 2020;94:91–5
35. Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, et al Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: A single-centered, retrospective, observational study Lancet Respir Medic. 2020;8:475–81
36. Yang ZY, Huang Y, Ganesh L, Leung K, Kong WP, Schwartz O, et al pH-dependent entry of severe acute respiratory syndrome coronavirus is mediated by the spike glycoprotein and enhanced by dendritic cell transfer through DC-SIGN J Virol. 2004;78:5642–50
37. Ramalingam S, Graham C, Dove J, Morrice L, Sheikh A. A pilot, open labelled, randomised controlled trial of hypertonic saline nasal irrigation and gargling for the common cold Sci Rep. 2019;9:1015
38. Quan FS, Rubino I, Lee SH, Koch B, Choi HJ. Universal and reusable virus deactivation system for respiratory protection Sci Rep. 2017;7:39956
39. Xu W, Xia S, Pu J, Wang Q, Li P, Lu L, et al The antihistamine drugs carbinoxamine maleate and chlorpheniramine maleate exhibit potent antiviral activity against a broad spectrum of influenza viruses Front Microbiol. 2018;9:2643
40. Wang H, Yang P, Liu K, Guo F, Zhang Y, Zhang G, et al SARS coronavirus entry into host cells through a novel clathrin- and caveolae-independent endocytic pathway Cell Res. 2008;18:290–301
41. Roland PS, Ryan MW, Wall GM. Olopatadine nasal spray for the treatment of seasonal allergic rhinitis in patients aged 6 years and older Expert Opin Pharmacother. 2010;11:1559–67
42. Cheng LH, Lee JC, Wu PC, Lin YY, Chu YH, Wang HW. Azelastine nasal spray inhibiting sympathetic function on human nasal mucosa in patients with allergy rhinitis Rhinology. 2019;57:268–72
43. Vincent MJ, Bergeron E, Benjannet S, Erickson BR, Rollin PE, Ksiazek TG, et al Chloroquine is a potent inhibitor of SARS coronavirus infection and spread Virol J. 2005;2:69
44. Savarino DA, Trani LD, Donatelli I, Cauda R, Cassone A. New insights into the antiviral effects of chloroquine Lancet Infect Dis. 2006;6:67–9
45. Hu TY, Frieman M, Wolfram J. Insights from nanomedicine into chloroquine efficacy against COVID-19 Nat Nanotechol. 2020;15:247–9
46. Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic treatments for coronavirus disease 2019 (COVID-19): A review JAMA. 2020 doi: 101001/jama20206019
47. Savarino A, Boelaert JR, Cassone A, Majori G, Cauda R. Effects of chloroquine on viral infections: An old drug against today's diseases? Lancet Infect Dis. 2003;3:722–7
48. Al-Bari MAA. Targeting endosomal acidification by chloroquine analogs as a promising strategy for the treatment of emerging viral diseases Pharmacol Res Perspect. 2017;5:e00293
49. Chen X, Li M, Li L, Xu S, Huang D, Ju M, et al Trehalose, sucrose and raffinose are novel activators of autophagy in human keratinocytes through an mTOR-independent pathway Sci Rep. 2016;6:28423
50. Shivakumar S, Panigrahi T, Shetty R, Subramani M, Ghosh A, Jeyabalan N. Chloroquine protects human corneal epithelial cells from desiccation stress induced inflammation without altering the autophagy flux Biomed Res Int. 2018;2018:7627329
51. Guillemard E, Geniteau-Legendre M, Kergot R, Lemaire G, Petit JF, Labarre C, et al Role of trehalose dimycolate-induced interferon-alpha/beta in the restriction of encephalomyocarditis virus growth in vivo
and in peritoneal macrophage cultures Antiviral Res. 1995;28:175–89
52. Yuan S, Zhang ZW, Li ZL. Trehalose may decrease the transmission of Zika virus to the fetus by activating degradative autophagy Front Cell Infect Microbiol. 2017;7:402
53. Hon S. Trehalose, an mTOR-independent Inducer of Autophagy, Inhibits HIV Infection in Primary Human Macrophage UC San Diego, UC San Diego Electronic Theses and Dissertations 2017Last accessed on 2020 May 18 Available from: https://escholarshiporg/uc/item/77j0q7gd
54. Tien NT, Karaca I, Tamboli IY, Walter J. Trehalose alters subcellular trafficking and the metabolism of the alzheimer-associated amyloid precursor protein J Biol Chem. 2016;291:10528–40
55. Panigrahi T, Shivakumar S, Shetty R, D'souza S, Nelson EJ, Sethu S, et al Trehalose augments autophagy to mitigate stress induced inflammation in human corneal cells Ocul Surf. 2019;17:699–713
56. Wu Q, Jiang D, Huang C, van Dyk LF, Li L, Chu HW. Trehalose-mediated autophagy impairs the anti-viral function of human primary airway epithelial cells PLoS One. 2015;10:e0124524
57. Matsuo T, Tsuchida Y, Morimoto N. Trehalose eye drops in the treatment of dry eye syndrome Ophthalmology. 2002;109:2024–9
58. Titiyal JS, Kaur M, Falera R, Bharghava A, Sah R, Sen S. Efficacy and safety of topical chloroquine in mild to moderate dry eye disease Curr Eye Res. 2019;44:1306–12
59. Bhavsar A, Bhavsar S, Jain S. Evaluation of the effects of chloroquine phosphate eye drops in patients with dry eye syndrome Int J Biomed Adv Res. 2011;2:198–214
60. Chiambaretta F, Doan S, Labetoulle M, Rocher N, Fekih LE, Messaoud R, et al A randomized, controlled study of the efficacy and safety of a new eyedrop formulation for moderate to severe dry eye syndrome Eur J Ophthalmol. 2017;27:1–9
61. Mishra S, Das S. Corneal ulcer following prolonged topical chloroquine phosphate Delhi J Ophthalm. 2018:2842–3 doi: 107869/djo355
62. Schmidl D, Schmetterer L, Witkowska KJ, Unterhuber A, dos Santos VA, Kaya S, et al Tear film thickness after treatment with artificial tears in patients with moderate dry eye disease Cornea. 2015;34:421–6
63. Kam KW, Chen LJ, Wat N, Young AL. Topical olopatadine in the treatment of allergic conjunctivitis: A systematic review and meta-analysis Ocul Immunol Inflamm. 2017;25:663–77
64. Mizoguchi T, Ozaki M, Ogino N. Efficacy of 005% epinastine and 01% olopatadine for allergic conjunctivitis as seasonal and preseasonal treatment Clin Ophthalmol. 2017;11:1747–53
65. Teijaro JR. Type I interferons in viral control and immune regulation Curr Opin Virol. 2016;16:31–40
66. Shalhoub S. Interferon beta-1b for COVID-19 Lancet. 2020 S0140-6736(20)31101-6 doi: 101016/S0140-6736(20)31101-6
67. Wang BX, Fish EN. Global virus outbreaks: Interferons as 1st responders Semin Immunol. 2019;43:101300
68. Zhou Q, Wei X-S, Xiang X, Wang X, Wang Z-H, Chen V, et al Interferon-a2b treatment for COVID-19 medRxiv. 2020 doi: 101101/2020040620042580
69. Nanji AA, Moon CS, Galor A, Sein J, Oellers P, Karp CL, et al Surgical versus medical treatment of ocular surface squamous neoplasia: A comparison of recurrences and complications Ophthalmology. 2014;121:994–1000
70. Kariwa H, Fujii N, Takashima I. Inactivation of SARS coronavirus by means of povidone-iodine, physical conditions and chemical reagents Dermatology. 2006;212(Suppl 1):119–23
71. Eggers M, Koburger-Janssen T, Eickmann M, Zorn J. In vitro
bactericidal and virucidal efficacy of povidone-iodine gargle/mouthwash against respiratory and oral tract pathogens Infect Dis Ther. 2018;7:249–59
72. Mady LJ, Kubik MW, Baddour K, Snyderman CH, Rowan NR. Consideration of povidone-iodine as a public health intervention for COVID-19: Utilization as “Personal Protective Equipment” for frontline providers exposed in high-risk head and neck and skull base oncology care Oral Oncol. 2020;105:104724
73. AAO. Special considerations for ophthalmic surgery during the COVID-19 pandemic. 2020Last accessed on 2020 May 15 Available from: https://wwwaaoorg/headline/special-considerations-ophthalmic-surgery-during-c
74. McLeod SD, Tham VM, Phan ST, Hwang DG, Rizen M, Abbott RL. Bilateral diffuse lamellar keratitis following bilateral simultaneous versus sequential laser in situ
keratomileusis Br J Ophthalmol. 2003;87:1086–7
75. Costedoat-Chalumeau N, Dunogue B, Leroux G, Morel N, Jallouli M, Le Guern V, et al A critical review of the effects of hydroxychloroquine and chloroquine on the eye Clin Rev Allergy Immunol. 2015;49:317–26
76. Marmor MF. COVID-19 and Chloroquine/Hydroxychloroquine: Is there ophthalmological concern? Am J Ophthalmol. 2020;213:A3–4
77. Azhdari M, Karandish M, Mansoori A. Metabolic benefits of curcumin supplementation in patients with metabolic syndrome: A systematic review and meta-analysis of randomized controlled trials Phytother Res. 2019;33:1289–301
78. Mathew D, Hsu W-L. Antiviral potential of curcumin J Funct Foods. 2018;40:692–9
79. Moghadamtousi SZ, Kadir HA, Hassandarvish P, Tajik H, Abubakar S, Zandi K, et al A review on antibacterial, antiviral, and antifungal activity of curcumin Biomed Res Int. 2014;2014:186864
80. Tabrizi R, Vakili S, Akbari M, Mirhosseini N, Lankarani KB, Rahimi M, et al The effects of curcumin-containing supplements on biomarkers of inflammation and oxidative stress: A systematic review and meta-analysis of randomized controlled trials Phytother Res. 2019;33:253–62
81. Wen CC, Kuo YH, Jan JT, Liang PH, Wang SY, Liu HG, et al Specific plant terpenoids and lignoids possess potent antiviral activities against severe acute respiratory syndrome coronavirus J Med Chem. 2007;50:4087–95
82. Hewlings SJ, Kalman DS. Curcumin: A review of its' effects on human health Foods. 2017;6:92
83. Smieszek SP, Przychodzen BP, Polymeropoulos MH. Amantadine disrupts lysosomal gene expression: A hypothesis for COVID19 treatment? Int J Antimicrob Agents. 2020:106004 doi: 10.1016/j.ijantimicag.2020
84. Daneshkhah A, Agrawal V, Eshein A, Subramanian H, Roy HK, Backman V. The possible role of vitamin D in suppressing cytokine storm and associated mortality in COVID-19 patients medRxiv. 2020Last accessed on 2020 May 18 doi: 101101/2020040820058578
85. Martens PJ, Gysemans C, Verstuyf A, Mathieu AC. Vitamin D's effect on immune function Nutrients. 2020;12:E1248
86. Greiller CL, Martineau AR. Modulation of the immune response to respiratory viruses by vitamin D Nutrients. 2015;7:4240–70
87. Galior K, Grebe S, Singh R. Development of vitamin D toxicity from overcorrection of vitamin D deficiency: A review of case reports Nutrients. 2018;10:953
88. Calder PC, Carr AC, Gombart AF, Eggersdorfer M. Optimal nutritional status for a well-functioning immune system is an important factor to protect against viral infections Nutrients. 2020;12:1181
89. Cramer H, Lauche R, Langhorst J, Dobos G. Is one yoga style better than another? A systematic review of associations of yoga style and conclusions in randomized yoga trials Complement Ther Med. 2016;25:178–87
90. Falkenberg RI, Eising C, Peters ML. Yoga and immune system functioning: A systematic review of randomized controlled trials J Behav Med. 2018;41:467–82
91. Chu P, Gotink RA, Yeh GY, Goldie SJ, Hunink MG. The effectiveness of yoga in modifying risk factors for cardiovascular disease and metabolic syndrome: A systematic review and meta-analysis of randomized controlled trials Eur J Prev Cardiol. 2016;23:291–307